A coordinated DNA damage response promotes adult quiescent neural stem cell activation
A coordinated DNA damage response promotes adult quiescent neural stem cell activation
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DOI：
10.1371/journal.pbio.2001264
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发表时间：
2017-05-01
期刊：
影响因子：
9.8
通讯作者：
Jeggo, Penny A.
中科院分区：
文献类型：
--
作者：
Barazzuol, Lara;Ju, Limei;Jeggo, Penny A.
干细胞和分化细胞对DNA损伤的反应经常不同，这可以决定组织的敏感性。通过利用洞察成年神经室下区（SVZ）在体内的子域的空间排列，我们表现出不同的反应，电离辐射（IR）之间的神经干细胞和祖细胞。此外，我们揭示了新生儿和成人神经干细胞（NSCs）之间不同的DNA损伤反应。2戈伊照射后，神经祖细胞（转运扩增细胞和神经母细胞）而非神经干细胞（静止和活化）发生凋亡。这种反应是细胞类型依赖性的，而不是增殖依赖性的，似乎并不受DNA损伤诱导或修复能力差异的驱动。此外，暴露于2戈伊IR促进增殖停滞和分化的成人SVZ。这3种反应是共济失调毛细血管扩张突变（ATM）依赖性的，并促进静止NSC（qNSC）激活，这不会发生在缺乏祖细胞的亚结构域。IR后产生的成神经细胞来源于活化的qNSC，而不是辐射的祖细胞，最大限度地减少了复制或有丝分裂造成的损伤。我们认为，细胞凋亡是一种快速细胞死亡的形式，而不是赋予敏感的细胞死亡，其作用是去除受损的祖细胞并促进qNSC活化。值得注意的是，新生儿（P5）SVZ的分析表明，虽然祖细胞仍然对凋亡敏感，但它们不能有效地阻止增殖。因此，它们的再增殖从辐射的祖细胞而不是通过qNSC活化迅速发生。
Stem and differentiated cells frequently differ in their response to DNA damage, which can determine tissue sensitivity. By exploiting insight into the spatial arrangement of subdomains within the adult neural subventricular zone (SVZ) in vivo, we show distinct responses to ionising radiation (IR) between neural stem and progenitor cells. Further, we reveal different DNA damage responses between neonatal and adult neural stem cells (NSCs). Neural progenitors (transit amplifying cells and neuroblasts) but not NSCs (quiescent and activated) undergo apoptosis after 2 Gy IR. This response is cell type-rather than proliferationdependent and does not appear to be driven by distinctions in DNA damage induction or repair capacity. Moreover, exposure to 2 Gy IR promotes proliferation arrest and differentiation in the adult SVZ. These 3 responses are ataxia telangiectasia mutated (ATM)dependent and promote quiescent NSC (qNSC) activation, which does not occur in the subdomains that lack progenitors. Neuroblasts arising post-IR derive from activated qNSCs rather than irradiated progenitors, minimising damage compounded by replication or mitosis. We propose that rather than conferring sensitive cell death, apoptosis is a form of rapid cell death that serves to remove damaged progenitors and promote qNSC activation. Significantly, analysis of the neonatal (P5) SVZ reveals that although progenitors remain sensitive to apoptosis, they fail to efficiently arrest proliferation. Consequently, their repopulation occurs rapidly from irradiated progenitors rather than via qNSC activation.